Novel mutations in TARDBP(TDP-43) in patients with familial amyotrophic lateral sclerosis

Nicola J. Rutherford, Yong Jie Zhang, Matt Baker, Jennifer M. Gass, NiCole A. Finch, Ya Fei Xu, Heather Stewart, Brendan J. Kelley, Karen Kuntz, Richard J P Crook, Jemeen Sreedharan, Caroline Vance, Eric Sorenson, Carol Lippa, Eileen H. Bigio, Daniel H. Geschwind, David S. Knopman, Hiroshi Mitsumoto, Ronald C. Petersen, Neil R. CashmanMike Hutton, Christopher E. Shaw, Kevin B. Boylan, Bradley Boeve, Neill R. Graff-Radford, Zbigniew K. Wszolek, Richard J. Caselli, Dennis W. Dickson, Ian R. Mackenzie, Leonard Petrucelli, Rosa Rademakers

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The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the ∼25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis.

Original languageEnglish (US)
Article numbere1000193
JournalPLoS genetics
Issue number9
StatePublished - Sep 2008

Bibliographical note

Funding Information:
Our initial study population comprised a total of 296 patients with TDP-43 related neurodegenerative diseases, including 176 clinically diagnosed patients with ALS, FTLD and FTLD-ALS and 120 patients with pathologically confirmed TDP-43 proteinopathy. The average age at onset in the clinical cohort was 57.8±10.7 (range 31–81 years) and the average age at death in the pathological cohort was 74.8±13.8 (range 38–100 years). Among patients with known ethnicities (N = 214), 95% were Caucasian (N = 203), 3% were Hispanic (N = 7) and 2% were others (African/American (N = 2), East-Indian (N = 1) and Caribbean (N = 1)). A summary of the primary diagnoses and family history of the patients is provided in . The majority of the pathological confirmed patients (N = 87) were derived from the Mayo Clinic Jacksonville Brain Bank and primarily ascertained through The State of Florida Alzheimer's Disease Initiative funded through the Department of Elder Affairs, The Einstein Aging Study, The Udall Center for Excellence in Parkinson's Disease Research, CurePSP/The Society for Progressive Supranuclear Palsy, the Mayo Alzheimer's Disease Patient Registry (ADPR) and the Florida Alzheimer's Disease Research Center (ADRC). Additional clinical and pathological confirmed patients were ascertained through the Mayo Clinic Jacksonville and Rochester ADRC (N = 60), Mayo Clinic Scottsdale Alzheimer's Disease Center (ADC) (N = 4), the Neurological Institute of New York, Columbia University (N = 2), the University of California, Los Angeles (UCLA) ADC (N = 23), the University of British Columbia (N = 58), the Harvard Brain Bank (N = 5), the Sun Health Research Institute (N = 4), the Drexel University College of Medicine (N = 1), the Northwestern Feinberg School of Medicine (N = 13) and the Coriell Institute for Medical Research (N = 39). A list of the specific samples from the Coriell Institute included in the TARDBP mutation screening is provided as .


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